First Thesis Advisor

Keywords

Abstract

Osteoarthritis (OA), a degenerative disease of articular joints, is the leading cause of chronic disability in the US and affects more than a third of adults over 65 years old. Due to the obesity epidemic and an aging population, the prevalence of OA is expected to rise in both young and old adults. There are no disease modifying OA drugs. Therefore, providing any treatment options that delay the onset or progression of OA is highly desirable. The scope of this dissertation examines two different strategies to promote translational therapies for OA. The first approach investigated whether Smad ubiquitin regulatory factor 2 (Smurf2), an E3 ubiquitin ligase, could be a potential therapeutic target for OA. The second approach examined the incorporation of small chemical residues to enhance the physical and bioactivity of a bioinert scaffold for cartilage tissue repair.

Overexpression of Smurf2 in chondrocytes was shown to accelerate spontaneous OA development in mice. We hypothesized that reduced Smurf2 expression could slow the progression of OA and enhance the performance of cells for cartilage repair. By performing surgical destabilization of the medial meniscus (DMM) on Smurf2-deficient mice, loss of Smurf2 was shown to mitigate OA changes in young mice but this protection diminished in older mice. Assessment of Smurf2-deficient chondrocytes in vitro revealed an upregulation of chondrogenic genes compared to wild-type; however, these differences were not seen at the protein level, deterring its potential use for cell-based therapies. During the course of this study, new insights about how age and sex affects different joint compartments in response to DMM surgery were also uncovered. These results broadened existing understanding of DMM-induced OA in mice but also questioned the validity of such a model to identify disease modifying targets that are translatable to OA in humans with advanced age.

Due to a lack of innate repair mechanisms in cartilage, damage to cartilage increases the risk of developing OA early. Tissue engineering provides a unique strategy for repairing damaged cartilage by delivering cells in a well-controlled environment that can promote the formation of neotissue. We hypothesized that synthetic chemical residues could enhance the mechanical properties of a bioinert scaffold and promote matrix production of encapsulated chondrocytes. Covalent incorporation of small anionic or zwitterionic chemical residues in a polyethylene glycol-based hydrogel improved its stiffness and resistance to fluid flow, however, the resulting physical environment can also exert a dominant negative effect on matrix production of encapsulated chondrocytes. These results suggest that modulating the biosynthesis of chondrocytes with biochemical signals requires a concurrent reduction in any conflicting mechanotransduction signaling, emphasizing the importance of a degradable system to promote new cartilage formation.

In summary, this dissertation establishes Smurf2 as a modulator of OA progression but implies that other factors such as age or protein(s) with redundant Smurf2 functions may play a role in limiting its effect as a therapeutic target. This work also reveals fundamental biology about how chondrocytes behave in response to physical and chemical cues in their microenvironment, which will aid in the design of better scaffolds for cartilage tissue engineering.